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BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2014

Open Access 01-12-2014 | Research article

The active form of MMP-3 is a marker of synovial inflammation and cartilage turnover in inflammatory joint diseases

Authors: Shu Sun, Anne-Christine Bay-Jensen, Morten A Karsdal, Anne Sofie Siebuhr, Qinlong Zheng, Walter P Maksymowych, Thorbjørn G Christiansen, Kim Henriksen

Published in: BMC Musculoskeletal Disorders | Issue 1/2014

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Abstract

Background

Matrix metalloproteinase-3 (MMP-3) plays an important role in the pathology of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Measurement of active MMP-3 in clinical samples could provide information about progression of rheumatoid diseases, and potentially response to treatment. Hence, we aimed to develop a sensitive assay specifically measuring the active form of MMP-3 (act-MMP-3) both in ex vivo models and in human sera.

Methods

A monoclonal antibody against the first 6 amino acids of act-MMP-3 was developed, and the specificity was carefully tested by comparing total and active MMP-3. A technically robust act-MMP-3 ELISA was produced. For biological validation, human synovial membrane and human cartilage explant (HEX) culture models were measured and compared by ELISA and immunoblots. For clinical relevance, the serum levels of act-MMP-3 in AS and RA patients before and after anti-TNF-α treatment were evaluated.

Results

A highly specific and technically robust ELISA detecting act-MMP-3 in serum was developed. The lower limit of detection was 33.7 pg/mL. The dilution and spiking recovery of human serum was within 100 ± 20%. The average intra- and inter-assay variations were 3.1% and 13.5% respectively.
High levels of act-MMP-3 expression were observed in human synovial membrane culture and oncostatin M and TNF-α stimulated human cartilage. In a cross-sectional study of both AS and RA patients, serum act-MMP-3 level was correlated with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). In addition, in patients receiving anti-TNF-α treatment, the serum level of act-MMP-3 was significantly reduced compared to baseline level reflecting the anti-inflammatory effects of the treatment.

Conclusion

We have successfully developed an assay measuring act-MMP-3 in human serum showing correlation to inflammatory markers. Further studies are required to clarify, whether act-MMP-3 can serve as a predictive marker for outcome in chronic rheumatoid disorders.
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Literature
1.
Braun J, Sieper J: Ankylosing spondylitis. Lancet. 2007, 369: 1379-1390. 10.1016/S0140-6736(07)60635-7.CrossRefPubMed
2.
Bay-Jensen AC, Leeming DJ, Kleyer A, Veidal SS, Schett G, Karsdal MA: Ankylosing spondylitis is characterized by an increased turnover of several different metalloproteinase-derived collagen species: a cross-sectional study. Rheumatol Int. 2012, 32: 3565-3572. 10.1007/s00296-011-2237-8.CrossRefPubMed
3.
Chen CH, Lin KC, Yu DT, Yang C, Huang F, Chen HA, Liang TH, Liao HT, Tsai CY, Wei JC, Chou CT: Serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in ankylosing spondylitis: MMP-3 is a reproducibly sensitive and specific biomarker of disease activity. Rheumatology (Oxford). 2006, 45: 414-420. 10.1093/rheumatology/kei208.CrossRef
4.
Yang C, Gu J, Rihl M, Baeten D, Huang F, Zhao M, Zhang H, Maksymowych WP, De KF, Veys EM, Yu DT: Serum levels of matrix metalloproteinase 3 and macrophage colony-stimulating factor 1 correlate with disease activity in ankylosing spondylitis. Arthritis Rheum. 2004, 51: 691-699. 10.1002/art.20696.CrossRefPubMed
5.
Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T: Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford). 2006, 45: 669-675. 10.1093/rheumatology/kel065.CrossRef
6.
Pap T, Muller-Ladner U, Gay RE, Gay S: Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res. 2000, 2: 361-367. 10.1186/ar113.CrossRefPubMedPubMedCentral
7.
Wu JJ, Lark MW, Chun LE, Eyre DR: Sites of stromelysin cleavage in collagen types II, IX, X, and XI of cartilage. J Biol Chem. 1991, 266: 5625-5628.PubMed
8.
Flannery CR, Lark MW, Sandy JD: Identification of a stromelysin cleavage site within the interglobular domain of human aggrecan. Evidence for proteolysis at this site in vivo in human articular cartilage. J Biol Chem. 1992, 267: 1008-1014.PubMed
9.
Knauper V, Wilhelm SM, Seperack PK, DeClerck YA, Langley KE, Osthues A, Tschesche H: Direct activation of human neutrophil procollagenase by recombinant stromelysin. Biochem J. 1993, 295 (Pt 2): 581-586.CrossRefPubMedPubMedCentral
10.
Shapiro SD, Fliszar CJ, Broekelmann TJ, Mecham RP, Senior RM, Welgus HG: Activation of the 92-kDa gelatinase by stromelysin and 4-aminophenylmercuric acetate. Differential processing and stabilization of the carboxyl-terminal domain by tissue inhibitor of metalloproteinases (TIMP). J Biol Chem. 1995, 270: 6351-6356. 10.1074/jbc.270.11.6351.CrossRefPubMed
11.
Suzuki K, Enghild JJ, Morodomi T, Salvesen G, Nagase H: Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin). Biochemistry. 1990, 29: 10261-10270. 10.1021/bi00496a016.CrossRefPubMed
12.
Knauper V, Lopez-Otin C, Smith B, Knight G, Murphy G: Biochemical characterization of human collagenase-3. J Biol Chem. 1996, 271: 1544-1550. 10.1074/jbc.271.3.1544.CrossRefPubMed
13.
Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003, 92: 827-839. 10.1161/01.RES.0000070112.80711.3D.CrossRefPubMed
14.
Nagase H, Enghild JJ, Suzuki K, Salvesen G: Stepwise activation mechanisms of the precursor of matrix metalloproteinase 3 (stromelysin) by proteinases and (4-aminophenyl)mercuric acetate. Biochemistry. 1990, 29: 5783-5789. 10.1021/bi00476a020.CrossRefPubMed
15.
Okada Y, Harris ED, Nagase H: The precursor of a metalloendopeptidase from human rheumatoid synovial fibroblasts. Purification and mechanisms of activation by endopeptidases and 4-aminophenylmercuric acetate. Biochem J. 1988, 254: 731-741.CrossRefPubMedPubMedCentral
16.
Kobayashi A, Naito S, Enomoto H, Shiomoi T, Kimura T, Obata K, Inoue K, Okada Y: Serum levels of matrix metalloproteinase 3 (stromelysin 1) for monitoring synovitis in rheumatoid arthritis. Arch Pathol Lab Med. 2007, 131: 563-570.PubMed
17.
Posthumus MD, Limburg PC, Westra J, Cats HA, Stewart RE, van Leeuwen MA, van Rijswijk MH: Serum levels of matrix metalloproteinase-3 in relation to the development of radiological damage in patients with early rheumatoid arthritis. Rheumatology (Oxford). 1999, 38: 1081-1087. 10.1093/rheumatology/38.11.1081.CrossRef
18.
Houseman M, Potter C, Marshall N, Lakey R, Cawston T, Griffiths I, Young-Min S, Isaacs JD: Baseline serum MMP-3 levels in patients with Rheumatoid Arthritis are still independently predictive of radiographic progression in a longitudinal observational cohort at 8 years follow up. Arthritis Res Ther. 2012, 14: R30-10.1186/ar3734.CrossRefPubMedPubMedCentral
19.
Maksymowych WP, Landewe R, Conner-Spady B, Dougados M, Mielants H, van der TH, Poole AR, Wang N, van der HD: Serum matrix metalloproteinase 3 is an independent predictor of structural damage progression in patients with ankylosing spondylitis. Arthritis Rheum. 2007, 56: 1846-1853. 10.1002/art.22589.CrossRefPubMed
20.
Lohmander LS, Hoerrner LA, Lark MW: Metalloproteinases, tissue inhibitor, and proteoglycan fragments in knee synovial fluid in human osteoarthritis. Arthritis Rheum. 1993, 36: 181-189. 10.1002/art.1780360207.CrossRefPubMed
21.
Hulejova H, Baresova V, Klezl Z, Polanska M, Adam M, Senolt L: Increased level of cytokines and matrix metalloproteinases in osteoarthritic subchondral bone. Cytokine. 2007, 38: 151-156. 10.1016/j.cyto.2007.06.001.CrossRefPubMed
22.
Obata K, Iwata K, Okada Y, Kohrin Y, Ohuchi E, Yoshida S, Shinmei M, Hayakawa T: A one-step sandwich enzyme immunoassay for human matrix metalloproteinase 3 (stromelysin-1) using monoclonal antibodies. Clin Chim Acta. 1992, 211: 59-72. 10.1016/0009-8981(92)90105-Y.CrossRefPubMed
23.
Barascuk N, Veidal SS, Larsen L, Larsen DV, Larsen MR, Wang J, Zheng Q, Xing R, Cao Y, Rasmussen LM, Karsdal MA: A novel assay for extracellular matrix remodeling associated with liver fibrosis: An enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen. Clin Biochem. 2010, 43: 899-904. 10.1016/j.clinbiochem.2010.03.012.CrossRefPubMed
24.
Gefter ML, Margulies DH, Scharff MD: A simple method for polyethylene glycol-promoted hybridization of mouse myeloma cells. Somatic Cell Genet. 1977, 3: 231-236. 10.1007/BF01551818.CrossRefPubMed
25.
Bay-Jensen AC, Liu Q, Byrjalsen I, Li Y, Wang J, Pedersen C, Leeming DJ, Dam EB, Zheng Q, Qvist P, Karsdal MA: Enzyme-linked immunosorbent assay (ELISAs) for metalloproteinase derived type II collagen neoepitope, CIIM–increased serum CIIM in subjects with severe radiographic osteoarthritis. Clin Biochem. 2011, 44: 423-429. 10.1016/j.clinbiochem.2011.01.001.CrossRefPubMed
26.
Bay-Jensen AC, Karsdal MA, Vassiliadis E, Wichuk S, Marcher-Mikkelsen K, Lories R, Christiansen C, Maksymowych WP: Circulating citrullinated vimentin fragments reflect disease burden in ankylosing spondylitis and have prognostic capacity for radiographic progression. Arthritis Rheum. 2013, 65: 972-980. 10.1002/art.37843.CrossRefPubMed
27.
Okada Y, Nagase H, Harris ED: A metalloproteinase from human rheumatoid synovial fibroblasts that digests connective tissue matrix components. Purification and characterization. J Biol Chem. 1986, 261: 14245-14255.PubMed
28.
Hui W, Rowan AD, Richards CD, Cawston TE: Oncostatin M in combination with tumor necrosis factor alpha induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo. Arthritis Rheum. 2003, 48: 3404-3418. 10.1002/art.11333.CrossRefPubMed
29.
Okada Y, Takeuchi N, Tomita K, Nakanishi I, Nagase H: Immunolocalization of matrix metalloproteinase 3 (stromelysin) in rheumatoid synovioblasts (B cells): correlation with rheumatoid arthritis. Ann Rheum Dis. 1989, 48: 645-653. 10.1136/ard.48.8.645.CrossRefPubMedPubMedCentral
30.
Baker AH, Edwards DR, Murphy G: Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci. 2002, 115: 3719-3727. 10.1242/jcs.00063.CrossRefPubMed
31.
Cawston TE, Mercer E: Preferential binding of collagenase to alpha 2-macroglobulin in the presence of the tissue inhibitor of metalloproteinases. FEBS Lett. 1986, 209: 9-12. 10.1016/0014-5793(86)81074-2.CrossRefPubMed
32.
Sottrup-Jensen L: Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation. J Biol Chem. 1989, 264: 11539-11542.PubMed
Metadata
Title
The active form of MMP-3 is a marker of synovial inflammation and cartilage turnover in inflammatory joint diseases
Authors
Shu Sun
Anne-Christine Bay-Jensen
Morten A Karsdal
Anne Sofie Siebuhr
Qinlong Zheng
Walter P Maksymowych
Thorbjørn G Christiansen
Kim Henriksen
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2014
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/1471-2474-15-93

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